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1. Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA

Author

Hansen, B, Vandriel, S, Vig, P, Garner, W, Mogul, D, Loomes, K, Piccoli, D, Rand, E, Jankowska, I, Czubkowski, P, Gliwicz-Miedzinska, D, Gonzales, E, Jacquemin, E, Bouligand, J, D'Antiga, L, Nicastro, E, Arnell, H, Fischler, B, Sokal, E, Demaret, T, Siew, S, Stormon, M, Karpen, S, Romero, R, Ebel, N, Feinstein, J, Roberts, A, Evans, H, Sundaram, S, Chaidez, A, Hardikar, W, Shankar, S, Fischer, R, Lacaille, F, Debray, D, Lin, H, Jensen, M, Jaramillo, C, Karthikeyan, P, Indolfi, G, Verkade, H, Larson-Nath, C, Quiros-Tejeira, R, Valentino, P, Rogalidou, M, Dezsofi, A, Squires, J, Schwarz, K, Calvo, P, Bernabeu, J, Zizzo, A, Nebbia, G, Bulut, P, Santos-Silva, E, Fawaz, R, Nastasio, S, Karnsakul, W, Tamara, M, Busoms, C, Kelly, D, Sandahl, T, Jimenez-Rivera, C, Banales, J, Mujawar, Q, Li, L, She, H, Wang, J, Kim, K, Oh, S, Sanchez, M, Cavalieri, M, Lee, W, Hajinicolaou, C, Lertudomphonwanit, C, Waisbourd-Zinman, O, Arikan, C, Alam, S, Carvalho, E, Melere, M, Eshun, J, Onal, Z, Desai, D, Wiecek, S, Pinto, R, Wolters, V, Garcia, J, Beretta, M, Kerkar, N, Brecelj, J, Rock, N, Lurz, E, Blondet, N, Shah, U, Thompson, R, Kamath, B, Hansen B. E., Vandriel S. M., Vig P., Garner W., Mogul D. B., Loomes K. M., Piccoli D. A., Rand E. B., Jankowska I., Czubkowski P., Gliwicz-Miedzinska D., Gonzales E. M., Jacquemin E., Bouligand J., D'Antiga L., Nicastro E., Arnell H., Fischler B., Sokal E., Demaret T., Siew S., Stormon M., Karpen S. J., Romero R., Ebel N. H., Feinstein J. A., Roberts A. J., Evans H. M., Sundaram S. S., Chaidez A., Hardikar W., Shankar S., Fischer R. T., Lacaille F., Debray D., Lin H. C., Jensen M. K., Jaramillo C., Karthikeyan P., Indolfi G., Verkade H. J., Larson-Nath C., Quiros-Tejeira R. E., Valentino P. L., Rogalidou M., Dezsofi A., Squires J. E., Schwarz K., Calvo P. L., Bernabeu J. Q., Zizzo A. N., Nebbia G., Bulut P., Santos-Silva E., Fawaz R., Nastasio S., Karnsakul W., Tamara M. L., Busoms C. M., Kelly D. A., Sandahl T. D., Jimenez-Rivera C., Banales J. M., Mujawar Q., Li L. -T., She H., Wang J. -S., Kim K. M., Oh S. H., Sanchez M. C., Cavalieri M. L., Lee W. S., Hajinicolaou C., Lertudomphonwanit C., Waisbourd-Zinman O., Arikan C., Alam S., Carvalho E., Melere M., Eshun J., Onal Z., Desai D. M., Wiecek S., Pinto R. B., Wolters V. M., Garcia J., Beretta M., Kerkar N., Brecelj J., Rock N., Lurz E., Blondet N., Shah U., Thompson R. J., Kamath B. M., Hansen, B, Vandriel, S, Vig, P, Garner, W, Mogul, D, Loomes, K, Piccoli, D, Rand, E, Jankowska, I, Czubkowski, P, Gliwicz-Miedzinska, D, Gonzales, E, Jacquemin, E, Bouligand, J, D'Antiga, L, Nicastro, E, Arnell, H, Fischler, B, Sokal, E, Demaret, T, Siew, S, Stormon, M, Karpen, S, Romero, R, Ebel, N, Feinstein, J, Roberts, A, Evans, H, Sundaram, S, Chaidez, A, Hardikar, W, Shankar, S, Fischer, R, Lacaille, F, Debray, D, Lin, H, Jensen, M, Jaramillo, C, Karthikeyan, P, Indolfi, G, Verkade, H, Larson-Nath, C, Quiros-Tejeira, R, Valentino, P, Rogalidou, M, Dezsofi, A, Squires, J, Schwarz, K, Calvo, P, Bernabeu, J, Zizzo, A, Nebbia, G, Bulut, P, Santos-Silva, E, Fawaz, R, Nastasio, S, Karnsakul, W, Tamara, M, Busoms, C, Kelly, D, Sandahl, T, Jimenez-Rivera, C, Banales, J, Mujawar, Q, Li, L, She, H, Wang, J, Kim, K, Oh, S, Sanchez, M, Cavalieri, M, Lee, W, Hajinicolaou, C, Lertudomphonwanit, C, Waisbourd-Zinman, O, Arikan, C, Alam, S, Carvalho, E, Melere, M, Eshun, J, Onal, Z, Desai, D, Wiecek, S, Pinto, R, Wolters, V, Garcia, J, Beretta, M, Kerkar, N, Brecelj, J, Rock, N, Lurz, E, Blondet, N, Shah, U, Thompson, R, Kamath, B, Hansen B. E., Vandriel S. M., Vig P., Garner W., Mogul D. B., Loomes K. M., Piccoli D. A., Rand E. B., Jankowska I., Czubkowski P., Gliwicz-Miedzinska D., Gonzales E. M., Jacquemin E., Bouligand J., D'Antiga L., Nicastro E., Arnell H., Fischler B., Sokal E., Demaret T., Siew S., Stormon M., Karpen S. J., Romero R., Ebel N. H., Feinstein J. A., Roberts A. J., Evans H. M., Sundaram S. S., Chaidez A., Hardikar W., Shankar S., Fischer R. T., Lacaille F., Debray D., Lin H. C., Jensen M. K., Jaramillo C., Karthikeyan P., Indolfi G., Verkade H. J., Larson-Nath C., Quiros-Tejeira R. E., Valentino P. L., Rogalidou M., Dezsofi A., Squires J. E., Schwarz K., Calvo P. L., Bernabeu J. Q., Zizzo A. N., Nebbia G., Bulut P., Santos-Silva E., Fawaz R., Nastasio S., Karnsakul W., Tamara M. L., Busoms C. M., Kelly D. A., Sandahl T. D., Jimenez-Rivera C., Banales J. M., Mujawar Q., Li L. -T., She H., Wang J. -S., Kim K. M., Oh S. H., Sanchez M. C., Cavalieri M. L., Lee W. S., Hajinicolaou C., Lertudomphonwanit C., Waisbourd-Zinman O., Arikan C., Alam S., Carvalho E., Melere M., Eshun J., Onal Z., Desai D. M., Wiecek S., Pinto R. B., Wolters V. M., Garcia J., Beretta M., Kerkar N., Brecelj J., Rock N., Lurz E., Blondet N., Shah U., Thompson R. J., and Kamath B. M.

Abstract

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study. APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, p

Published
2024

4. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study

Author

Vandriel, S, Li, L, She, H, Wang, J, Gilbert, M, Jankowska, I, Czubkowski, P, Gliwicz-Miedzinska, D, Gonzales, E, Jacquemin, E, Bouligand, J, Spinner, N, Loomes, K, Piccoli, D, D'Antiga, L, Nicastro, E, Sokal, A, Demaret, T, Ebel, N, Feinstein, J, Fawaz, R, Nastasio, S, Lacaille, F, Debray, D, Arnell, H, Fischler, B, Siew, S, Stormon, M, Karpen, S, Romero, R, Kim, K, Baek, W, Hardikar, W, Shankar, S, Roberts, A, Evans, H, Jensen, M, Kavan, M, Sundaram, S, Chaidez, A, Karthikeyan, P, Sanchez, M, Cavalieri, M, Verkade, H, Lee, W, Squires, J, Hajinicolaou, C, Lertudomphonwanit, C, Fischer, R, Larson-Nath, C, Mozer-Glassberg, Y, Arikan, C, Lin, H, Bernabeu, J, Alam, S, Kelly, D, Carvalho, E, Ferreira, C, Indolfi, G, Quiros-Tejeira, R, Bulut, P, Calvo, P, Anal, Z, Valentino, P, Desai, D, Eshun, J, Rogalidou, M, Dezsofi, A, Wiecek, S, Nebbia, G, Pinto, R, Wolters, V, Tamara, M, Zizzo, A, Garcia, J, Schwarz, K, Beretta, M, Sandahl, T, Jimenez-Rivera, C, Kerkar, N, Brecelj, J, Mujawar, Q, Rock, N, Busoms, C, Karnsakul, W, Lurz, E, Santos-Silva, E, Blondet, N, Bujanda, L, Shah, U, Thompson, R, Hansen, B, Kamath, B, Vandriel S. M., Li L. -T., She H., Wang J. -S., Gilbert M. A., Jankowska I., Czubkowski P., Gliwicz-Miedzinska D., Gonzales E. M., Jacquemin E., Bouligand J., Spinner N. B., Loomes K. M., Piccoli D. A., D'Antiga L., Nicastro E., Sokal A., Demaret T., Ebel N. H., Feinstein J. A., Fawaz R., Nastasio S., Lacaille F., Debray D., Arnell H., Fischler B., Siew S., Stormon M., Karpen S. J., Romero R., Kim K. M., Baek W. Y., Hardikar W., Shankar S., Roberts A. J., Evans H. M., Jensen M. K., Kavan M., Sundaram S. S., Chaidez A., Karthikeyan P., Sanchez M. C., Cavalieri M. L., Verkade H. J., Lee W. S., Squires J. E., Hajinicolaou C., Lertudomphonwanit C., Fischer R. T., Larson-Nath C., Mozer-Glassberg Y., Arikan C., Lin H. C., Bernabeu J. Q., Alam S., Kelly D. A., Carvalho E., Ferreira C. T., Indolfi G., Quiros-Tejeira R. E., Bulut P., Calvo P. L., Anal Z., Valentino P. L., Desai D. M., Eshun J., Rogalidou M., Dezsofi A., Wiecek S., Nebbia G., Pinto R. B., Wolters V. M., Tamara M. L., Zizzo A. N., Garcia J., Schwarz K., Beretta M., Sandahl T. D., Jimenez-Rivera C., Kerkar N., Brecelj J., Mujawar Q., Rock N., Busoms C. M., Karnsakul W., Lurz E., Santos-Silva E., Blondet N., Bujanda L., Shah U., Thompson R. J., Hansen B. E., Kamath B. M., Vandriel, S, Li, L, She, H, Wang, J, Gilbert, M, Jankowska, I, Czubkowski, P, Gliwicz-Miedzinska, D, Gonzales, E, Jacquemin, E, Bouligand, J, Spinner, N, Loomes, K, Piccoli, D, D'Antiga, L, Nicastro, E, Sokal, A, Demaret, T, Ebel, N, Feinstein, J, Fawaz, R, Nastasio, S, Lacaille, F, Debray, D, Arnell, H, Fischler, B, Siew, S, Stormon, M, Karpen, S, Romero, R, Kim, K, Baek, W, Hardikar, W, Shankar, S, Roberts, A, Evans, H, Jensen, M, Kavan, M, Sundaram, S, Chaidez, A, Karthikeyan, P, Sanchez, M, Cavalieri, M, Verkade, H, Lee, W, Squires, J, Hajinicolaou, C, Lertudomphonwanit, C, Fischer, R, Larson-Nath, C, Mozer-Glassberg, Y, Arikan, C, Lin, H, Bernabeu, J, Alam, S, Kelly, D, Carvalho, E, Ferreira, C, Indolfi, G, Quiros-Tejeira, R, Bulut, P, Calvo, P, Anal, Z, Valentino, P, Desai, D, Eshun, J, Rogalidou, M, Dezsofi, A, Wiecek, S, Nebbia, G, Pinto, R, Wolters, V, Tamara, M, Zizzo, A, Garcia, J, Schwarz, K, Beretta, M, Sandahl, T, Jimenez-Rivera, C, Kerkar, N, Brecelj, J, Mujawar, Q, Rock, N, Busoms, C, Karnsakul, W, Lurz, E, Santos-Silva, E, Blondet, N, Bujanda, L, Shah, U, Thompson, R, Hansen, B, Kamath, B, Vandriel S. M., Li L. -T., She H., Wang J. -S., Gilbert M. A., Jankowska I., Czubkowski P., Gliwicz-Miedzinska D., Gonzales E. M., Jacquemin E., Bouligand J., Spinner N. B., Loomes K. M., Piccoli D. A., D'Antiga L., Nicastro E., Sokal A., Demaret T., Ebel N. H., Feinstein J. A., Fawaz R., Nastasio S., Lacaille F., Debray D., Arnell H., Fischler B., Siew S., Stormon M., Karpen S. J., Romero R., Kim K. M., Baek W. Y., Hardikar W., Shankar S., Roberts A. J., Evans H. M., Jensen M. K., Kavan M., Sundaram S. S., Chaidez A., Karthikeyan P., Sanchez M. C., Cavalieri M. L., Verkade H. J., Lee W. S., Squires J. E., Hajinicolaou C., Lertudomphonwanit C., Fischer R. T., Larson-Nath C., Mozer-Glassberg Y., Arikan C., Lin H. C., Bernabeu J. Q., Alam S., Kelly D. A., Carvalho E., Ferreira C. T., Indolfi G., Quiros-Tejeira R. E., Bulut P., Calvo P. L., Anal Z., Valentino P. L., Desai D. M., Eshun J., Rogalidou M., Dezsofi A., Wiecek S., Nebbia G., Pinto R. B., Wolters V. M., Tamara M. L., Zizzo A. N., Garcia J., Schwarz K., Beretta M., Sandahl T. D., Jimenez-Rivera C., Kerkar N., Brecelj J., Mujawar Q., Rock N., Busoms C. M., Karnsakul W., Lurz E., Santos-Silva E., Blondet N., Bujanda L., Shah U., Thompson R. J., Hansen B. E., and Kamath B. M.

Abstract

Background and Aims: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. Approach and Results: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver (p < 0.001). Conclusions: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.

Published
2023

5. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study

Author

Vandriel, SM, Li, L-T, She, H, Wang, J-S, Gilbert, MA, Jankowska, I, Czubkowski, P, Gliwicz-Miedzinska, D, Gonzales, EM, Jacquemin, E, Bouligand, J, Spinner, NB, Loomes, KM, Piccoli, DA, D'Antiga, L, Nicastro, E, Sokal, E, Demaret, T, Ebel, NH, Feinstein, JA, Fawaz, R, Nastasio, S, Lacaille, F, Debray, D, Arnell, H, Fischler, B, Siew, S, Stormon, M, Karpen, SJ, Romero, R, Kim, KM, Baek, WY, Hardikar, W, Shankar, S, Roberts, AJ, Evans, HM, Jensen, MK, Kavan, M, Sundaram, SS, Chaidez, A, Karthikeyan, P, Sanchez, MC, Cavalieri, ML, Verkade, HJ, Lee, WS, Squires, JE, Hajinicolaou, C, Lertudomphonwanit, C, Fischer, RT, Larson-Nath, C, Mozer-Glassberg, Y, Arikan, C, Lin, HC, Bernabeu, JQ, Alam, S, Kelly, DA, Carvalho, E, Ferreira, CT, Indolfi, G, Quiros-Tejeira, RE, Bulut, P, Calvo, PL, Onal, Z, Valentino, PL, Desai, DM, Eshun, J, Rogalidou, M, Dezsofi, A, Wiecek, S, Nebbia, G, Pinto, RB, Wolters, VM, Tamara, ML, Zizzo, AN, Garcia, J, Schwarz, K, Beretta, M, Sandahl, TD, Jimenez-Rivera, C, Kerkar, N, Brecelj, J, Mujawar, Q, Rock, N, Busoms, CM, Karnsakul, W, Lurz, E, Santos-Silva, E, Blondet, N, Bujanda, L, Shah, U, Thompson, RJ, Hansen, BE, Kamath, BM, Vandriel, SM, Li, L-T, She, H, Wang, J-S, Gilbert, MA, Jankowska, I, Czubkowski, P, Gliwicz-Miedzinska, D, Gonzales, EM, Jacquemin, E, Bouligand, J, Spinner, NB, Loomes, KM, Piccoli, DA, D'Antiga, L, Nicastro, E, Sokal, E, Demaret, T, Ebel, NH, Feinstein, JA, Fawaz, R, Nastasio, S, Lacaille, F, Debray, D, Arnell, H, Fischler, B, Siew, S, Stormon, M, Karpen, SJ, Romero, R, Kim, KM, Baek, WY, Hardikar, W, Shankar, S, Roberts, AJ, Evans, HM, Jensen, MK, Kavan, M, Sundaram, SS, Chaidez, A, Karthikeyan, P, Sanchez, MC, Cavalieri, ML, Verkade, HJ, Lee, WS, Squires, JE, Hajinicolaou, C, Lertudomphonwanit, C, Fischer, RT, Larson-Nath, C, Mozer-Glassberg, Y, Arikan, C, Lin, HC, Bernabeu, JQ, Alam, S, Kelly, DA, Carvalho, E, Ferreira, CT, Indolfi, G, Quiros-Tejeira, RE, Bulut, P, Calvo, PL, Onal, Z, Valentino, PL, Desai, DM, Eshun, J, Rogalidou, M, Dezsofi, A, Wiecek, S, Nebbia, G, Pinto, RB, Wolters, VM, Tamara, ML, Zizzo, AN, Garcia, J, Schwarz, K, Beretta, M, Sandahl, TD, Jimenez-Rivera, C, Kerkar, N, Brecelj, J, Mujawar, Q, Rock, N, Busoms, CM, Karnsakul, W, Lurz, E, Santos-Silva, E, Blondet, N, Bujanda, L, Shah, U, Thompson, RJ, Hansen, BE, and Kamath, BM

Abstract

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. APPROACH AND RESULTS: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001). CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.

Published
2023

6. Natural history of liver disease in a large international cohort of children with Alagille syndrome: results from The GALA Study

Author

Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Vandriel, S.M.; Li, L.T.; She, H.; Wang, J.S.; Gilbert, M.A.; Jankowska, I.; Czubkowski, P.; Gliwicz-Miedzi?ska, D.; Gonzales, E.M.; Jacquemin, E.; Bouligand, J.; Spinner, N.B.; Loomes, K.M.; Piccoli, D.A.; D'Antiga, L.; Nicastro, E.; Sokal, É.; Demaret, T.; Ebel, N.H.; Feinstein, J.A.; Fawaz, R.; Nastasio, S.; Lacaille, F.; Debray, D.; Arnell, H.; Fischler, B.; Siew, S.; Stormon, M.; Karpen, S.J.; Romero, R.; Kim, K.M.; Baek, W.Y.; Hardikar, W.; Shankar, S.; Roberts, A.J.; Evans, H.M.; Jensen, M.K.; Kavan, M.; Sundaram, S.S.; Chaidez, A.; Karthikeyan, P.; Sanchez, M.C.; Cavalieri, M.L.; Verkade, H.J.; Lee, W.S.; Squires, J.E.; Hajinicolaou, C.; Lertudomphonwanit, C.; Fischer, R.T.; Larson-Nath, C.; Mozer-Glassberg, Y.; Lin, H.C.; Quintero, Bernabeu J.; Alam, S.; Kelly, D.; Carvalho, E.; Ferreira, C.T.; Indolfi, G.; Quiros-Tejeira, R.E.; Bulut, P.; Calvo, P.L.; Önal, Z.; Valentino, P.L.; Desai, D.M.; Eshun, J.; Rogalidou, M.; Dezs?fi, A.; Wiecek, S.; Nebbia, G.; Borges Pinto, R.; Wolters, V.M.; Tamara, M.L.; Zizzo, A.N.; Garcia, J.; Schwarz, K.; Beretta, M.; Sandahl, T.D.; Jimenez-Rivera, C.; Kerkar, N.; Brecelj, J.; Mujawar, Q.; Rock, N.; Busoms, C.M.; Karnsakul, W.; Lurz, E.; Santos-Silva, E.; Blondet, N.; Bujanda, L.; Shah, U.; Thompson, R.J.; Hansen, B.E.; Kamath, B.M.; Global ALagille Alliance (GALA) Study Group, Koç University Hospital, School of Medicine, Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Vandriel, S.M.; Li, L.T.; She, H.; Wang, J.S.; Gilbert, M.A.; Jankowska, I.; Czubkowski, P.; Gliwicz-Miedzi?ska, D.; Gonzales, E.M.; Jacquemin, E.; Bouligand, J.; Spinner, N.B.; Loomes, K.M.; Piccoli, D.A.; D'Antiga, L.; Nicastro, E.; Sokal, É.; Demaret, T.; Ebel, N.H.; Feinstein, J.A.; Fawaz, R.; Nastasio, S.; Lacaille, F.; Debray, D.; Arnell, H.; Fischler, B.; Siew, S.; Stormon, M.; Karpen, S.J.; Romero, R.; Kim, K.M.; Baek, W.Y.; Hardikar, W.; Shankar, S.; Roberts, A.J.; Evans, H.M.; Jensen, M.K.; Kavan, M.; Sundaram, S.S.; Chaidez, A.; Karthikeyan, P.; Sanchez, M.C.; Cavalieri, M.L.; Verkade, H.J.; Lee, W.S.; Squires, J.E.; Hajinicolaou, C.; Lertudomphonwanit, C.; Fischer, R.T.; Larson-Nath, C.; Mozer-Glassberg, Y.; Lin, H.C.; Quintero, Bernabeu J.; Alam, S.; Kelly, D.; Carvalho, E.; Ferreira, C.T.; Indolfi, G.; Quiros-Tejeira, R.E.; Bulut, P.; Calvo, P.L.; Önal, Z.; Valentino, P.L.; Desai, D.M.; Eshun, J.; Rogalidou, M.; Dezs?fi, A.; Wiecek, S.; Nebbia, G.; Borges Pinto, R.; Wolters, V.M.; Tamara, M.L.; Zizzo, A.N.; Garcia, J.; Schwarz, K.; Beretta, M.; Sandahl, T.D.; Jimenez-Rivera, C.; Kerkar, N.; Brecelj, J.; Mujawar, Q.; Rock, N.; Busoms, C.M.; Karnsakul, W.; Lurz, E.; Santos-Silva, E.; Blondet, N.; Bujanda, L.; Shah, U.; Thompson, R.J.; Hansen, B.E.; Kamath, B.M.; Global ALagille Alliance (GALA) Study Group, Koç University Hospital, and School of Medicine

Abstract

Background and aims: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. Approach and results: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced >= 1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and <= 12 months) with median total bilirubin (TB) levels between >= 5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those >= 10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those 10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to >= 5.0 mg/dl, with 79% reaching adulthood with native liver (p < 0.001). Conclusions: in this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies., This study received funding support from the following agencies: The Alagille Syndrome Alliance, Mirum Pharmaceuticals Inc. and Albireo Pharma, Inc. who provided unrestricted educational grants to the Hospital for Sick Children (SickKids Foundation). The study sponsors were not involved in the conduct of the research study or preparation of the manuscript.

Published
2022

10. Aiming higher with Khaya.

Author

Adu, Gustav and Eshun, J. F.

Subjects
LUMBER industry & the environment, KHAYA, LUMBERING, FOREST products industry & the environment, LUMBER industry, LUMBER, GLOBAL warming, ENVIRONMENTAL impact analysis
Abstract

The article presents a study on the environmental impact of Khaya lumber production in Ghana. Topics include the materials and the procedures used in the study that aim to understand the components of the lumber, data that shows the environmental impacts including global warming potential and human toxicity of Khaya lumber manufacturing companies. Also discussed is the result of the study revealing the high environmental impact of using fossil fuels in processing Khaya lumber.

Published
2016

11. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study

Author

Shannon M, Vandriel, Li-Ting, Li, Huiyu, She, Jian-She, Wang, Melissa A, Gilbert, Irena, Jankowska, Piotr, Czubkowski, Dorota, Gliwicz-Miedzińska, Emmanuel M, Gonzales, Emmanuel, Jacquemin, Jérôme, Bouligand, Nancy B, Spinner, Kathleen M, Loomes, David A, Piccoli, Lorenzo, D'Antiga, Emanuele, Nicastro, Étienne, Sokal, Tanguy, Demaret, Noelle H, Ebel, Jeffrey A, Feinstein, Rima, Fawaz, Silvia, Nastasio, Florence, Lacaille, Dominique, Debray, Henrik, Arnell, Björn, Fischler, Susan, Siew, Michael, Stormon, Saul J, Karpen, Rene, Romero, Kyung Mo, Kim, Woo Yim, Baek, Winita, Hardikar, Sahana, Shankar, Amin J, Roberts, Helen M, Evans, M Kyle, Jensen, Marianne, Kavan, Shikha S, Sundaram, Alexander, Chaidez, Palaniswamy, Karthikeyan, Maria Camila, Sanchez, Maria Lorena, Cavalieri, Henkjan J, Verkade, Way Seah, Lee, James E, Squires, Christina, Hajinicolaou, Chatmanee, Lertudomphonwanit, Ryan T, Fischer, Catherine, Larson-Nath, Yael, Mozer-Glassberg, Cigdem, Arikan, Henry C, Lin, Jesus Quintero, Bernabeu, Seema, Alam, Deirdre A, Kelly, Elisa, Carvalho, Cristina Targa, Ferreira, Giuseppe, Indolfi, Ruben E, Quiros-Tejeira, Pinar, Bulut, Pier Luigi, Calvo, Zerrin, Önal, Pamela L, Valentino, Dev M, Desai, John, Eshun, Maria, Rogalidou, Antal, Dezsőfi, Sabina, Wiecek, Gabriella, Nebbia, Raquel Borges, Pinto, Victorien M, Wolters, María Legarda, Tamara, Andréanne N, Zizzo, Jennifer, Garcia, Kathleen, Schwarz, Marisa, Beretta, Thomas Damgaard, Sandahl, Carolina, Jimenez-Rivera, Nanda, Kerkar, Jernej, Brecelj, Quais, Mujawar, Nathalie, Rock, Cristina Molera, Busoms, Wikrom, Karnsakul, Eberhard, Lurz, Ermelinda, Santos-Silva, Niviann, Blondet, Luis, Bujanda, Uzma, Shah, Richard J, Thompson, Bettina E, Hansen, Binita M, Kamath, Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Vandriel, S.M., Li, L.T., She, H., Wang, J.S., Gilbert, M.A., Jankowska, I., Czubkowski, P., Gliwicz-Miedzi?ska, D., Gonzales, E.M., Jacquemin, E., Bouligand, J., Spinner, N.B., Loomes, K.M., Piccoli, D.A., D'Antiga, L., Nicastro, E., Sokal, É., Demaret, T., Ebel, N.H., Feinstein, J.A., Fawaz, R., Nastasio, S., Lacaille, F., Debray, D., Arnell, H., Fischler, B., Siew, S., Stormon, M., Karpen, S.J., Romero, R., Kim, K.M., Baek, W.Y., Hardikar, W., Shankar, S., Roberts, A.J., Evans, H.M., Jensen, M.K., Kavan, M., Sundaram, S.S., Chaidez, A., Karthikeyan, P., Sanchez, M.C., Cavalieri, M.L., Verkade, H.J., Lee, W.S., Squires, J.E., Hajinicolaou, C., Lertudomphonwanit, C., Fischer, R.T., Larson-Nath, C., Mozer-Glassberg, Y., Lin, H.C., Quintero, Bernabeu J., Alam, S., Kelly, D., Carvalho, E., Ferreira, C.T., Indolfi, G., Quiros-Tejeira, R.E., Bulut, P., Calvo, P.L., Önal, Z., Valentino, P.L., Desai, D.M., Eshun, J., Rogalidou, M., Dezs?fi, A., Wiecek, S., Nebbia, G., Borges Pinto, R., Wolters, V.M., Tamara, M.L., Zizzo, A.N., Garcia, J., Schwarz, K., Beretta, M., Sandahl, T.D., Jimenez-Rivera, C., Kerkar, N., Brecelj, J., Mujawar, Q., Rock, N., Busoms, C.M., Karnsakul, W., Lurz, E., Santos-Silva, E., Blondet, N., Bujanda, L., Shah, U., Thompson, R.J., Hansen, B.E., Kamath, B.M., Global ALagille Alliance (GALA) Study Group, Koç University Hospital, School of Medicine, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique

Subjects
Male, Cholestasis, Alagille syndrome, Bile duct atresia, Intrahepatic cholestasis, Hepatology, Hypertension, Portal/etiology, Gastroenterology and hepatology, Alagille Syndrome/epidemiology, Humans, Female, Child, Retrospective Studies
Abstract

Background and aims: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. Approach and results: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced >= 1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and = 5.0 and = 10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those 10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to = 5.0 mg/dl, with 79% reaching adulthood with native liver (p < 0.001). Conclusions: in this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB, This study received funding support from the following agencies: The Alagille Syndrome Alliance, Mirum Pharmaceuticals Inc. and Albireo Pharma, Inc. who provided unrestricted educational grants to the Hospital for Sick Children (SickKids Foundation). The study sponsors were not involved in the conduct of the research study or preparation of the manuscript.

Published
2022

12. Identifying Sample Provenance From SEM/EDS Automated Particle Analysis via Few-Shot Learning Coupled With Similarity Graph Clustering.

Author

Eshun J, Lamar NC, Aksoy SG, Akers S, Garcia B, Cunningham H, Chin G Jr, and Bilbrey JA

Abstract

Automated particle analysis (APA) provides a vast amount of compositional data via energy-dispersive X-ray spectroscopy along with size and shape data via scanning electron microscopy for individual particles in a sample. In many instances, APA data are leveraged to support identification of the source of a sample based on the detection of particles of a specific composition. Often, the particles that provide context make up a minuscule portion of the sample. Additionally, the interpretation of complex samples can be difficult due to the diversity of compositions both in the mixture and within a particle. In this work, we demonstrate a method to compute and cluster similarity graphs that describe inter-particle relationships within a sample using a multi-modal few-shot learning neural network. As a proof-of-concept, we show that samples known to have been exposed to gunshot residue can be distinguished from samples occasionally mistaken for gunshot residue. Our workflow builds upon standard APA techniques and data processing methods to unveil additional information in a readily interpretable and quantitatively comparable format., Competing Interests: Conflict of Interest: The authors declare that they have no competing interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Microscopy Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Published
2024
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13. Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA.

Author

Hansen BE, Vandriel SM, Vig P, Garner W, Mogul DB, Loomes KM, Piccoli DA, Rand EB, Jankowska I, Czubkowski P, Gliwicz-Miedzińska D, Gonzales EM, Jacquemin E, Bouligand J, D'Antiga L, Nicastro E, Arnell H, Fischler B, Sokal É, Demaret T, Siew S, Stormon M, Karpen SJ, Romero R, Ebel NH, Feinstein JA, Roberts AJ, Evans HM, Sundaram SS, Chaidez A, Hardikar W, Shankar S, Fischer RT, Lacaille F, Debray D, Lin HC, Jensen MK, Jaramillo C, Karthikeyan P, Indolfi G, Verkade HJ, Larson-Nath C, Quiros-Tejeira RE, Valentino PL, Rogalidou M, Dezsőfi A, Squires JE, Schwarz K, Calvo PL, Bernabeu JQ, Zizzo AN, Nebbia G, Bulut P, Santos-Silva E, Fawaz R, Nastasio S, Karnsakul W, Tamara ML, Busoms CM, Kelly DA, Sandahl TD, Jimenez-Rivera C, Banales JM, Mujawar Q, Li LT, She H, Wang JS, Kim KM, Oh SH, Sanchez MC, Cavalieri ML, Lee WS, Hajinicolaou C, Lertudomphonwanit C, Waisbourd-Zinman O, Arikan C, Alam S, Carvalho E, Melere M, Eshun J, Önal Z, Desai DM, Wiecek S, Pinto RB, Wolters VM, Garcia J, Beretta M, Kerkar N, Brecelj J, Rock N, Lurz E, Blondet N, Shah U, Thompson RJ, and Kamath BM

Subjects
Humans, Female, Male, Retrospective Studies, Child, Infant, Child, Preschool, Progression-Free Survival, Adolescent, Carrier Proteins, Membrane Glycoproteins, Alagille Syndrome complications, Alagille Syndrome drug therapy
Abstract

Background and Aims: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study., Approach and Results: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings., Conclusions: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Published
2024
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14. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study.

Author

Vandriel SM, Li LT, She H, Wang JS, Gilbert MA, Jankowska I, Czubkowski P, Gliwicz-Miedzińska D, Gonzales EM, Jacquemin E, Bouligand J, Spinner NB, Loomes KM, Piccoli DA, D'Antiga L, Nicastro E, Sokal É, Demaret T, Ebel NH, Feinstein JA, Fawaz R, Nastasio S, Lacaille F, Debray D, Arnell H, Fischler B, Siew S, Stormon M, Karpen SJ, Romero R, Kim KM, Baek WY, Hardikar W, Shankar S, Roberts AJ, Evans HM, Jensen MK, Kavan M, Sundaram SS, Chaidez A, Karthikeyan P, Sanchez MC, Cavalieri ML, Verkade HJ, Lee WS, Squires JE, Hajinicolaou C, Lertudomphonwanit C, Fischer RT, Larson-Nath C, Mozer-Glassberg Y, Arikan C, Lin HC, Bernabeu JQ, Alam S, Kelly DA, Carvalho E, Ferreira CT, Indolfi G, Quiros-Tejeira RE, Bulut P, Calvo PL, Önal Z, Valentino PL, Desai DM, Eshun J, Rogalidou M, Dezsőfi A, Wiecek S, Nebbia G, Pinto RB, Wolters VM, Tamara ML, Zizzo AN, Garcia J, Schwarz K, Beretta M, Sandahl TD, Jimenez-Rivera C, Kerkar N, Brecelj J, Mujawar Q, Rock N, Busoms CM, Karnsakul W, Lurz E, Santos-Silva E, Blondet N, Bujanda L, Shah U, Thompson RJ, Hansen BE, and Kamath BM

Subjects
Humans, Child, Male, Female, Retrospective Studies, Alagille Syndrome epidemiology, Cholestasis, Hypertension, Portal etiology
Abstract

Background and Aims: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS., Approach and Results: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001)., Conclusions: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of American Association for the Study of Liver Diseases.)

Published
2023
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15. Targeting plasma cells with daratumumab aids in the treatment of post-transplant autoimmune-like hepatitis.

Author

Epperly R, Santiago T, Morin CE, Patton K, Deyo J, Eshun J, Triplett B, and Sharma A

Subjects
Adolescent, Humans, Male, Antibodies, Monoclonal therapeutic use, Hematopoietic Stem Cell Transplantation adverse effects, Hepatitis, Autoimmune drug therapy, Hepatitis, Autoimmune etiology, Plasma Cells drug effects
Abstract

Antibody-mediated autoimmune-like hepatitis is a rare and challenging occurrence after hematopoietic cell transplant (HCT). We present the case of a 16-year-old male patient with Ph+ ALL who underwent matched sibling donor HCT and developed autoimmune-like hepatitis after receiving ponatinib for post-HCT maintenance, evidenced by marked plasma cell infiltrate on liver biopsy. He was successfully treated with steroids and daratumumab, an anti-CD38-monoclonal antibody. The dramatic response in this patient warrants expanded investigation of daratumumab for plasma cell-mediated disorders post-HCT. It further highlights that identifying mechanisms of immune-mediated injury can allow for directed therapy and limit exposure to broad immune suppression., (© 2021 Wiley Periodicals LLC.)

Published
2021
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16. Identical twins with XLA requiring differing amounts of 20% subcutaneous immunoglobulin secondary to protein-losing enteropathy.

Author

Lan J, Eshun J, and Lieberman JA

Subjects
Adolescent, Agammaglobulinemia diagnosis, Body Weight, Disease Progression, Drug Dosage Calculations, Genetic Diseases, X-Linked diagnosis, Humans, Immunoglobulin G blood, Infusions, Subcutaneous, Male, Twins, Monozygotic, Agammaglobulinemia therapy, Genetic Diseases, X-Linked therapy, Immunoglobulins therapeutic use, Inflammatory Bowel Diseases diagnosis, Protein-Losing Enteropathies therapy
Published
2018
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17. Comparison of immunohistochemistry and silver stain for the diagnosis of pediatric Helicobacter pylori infection in urease-negative gastric biopsies.

Author

Eshun JK, Black DD, Casteel HB, Horn H, Beavers-May T, Jetton CA, and Parham DM

Subjects
Adolescent, Adult, Biopsy, Child, Child, Preschool, Chronic Disease, Gastritis enzymology, Gastritis microbiology, Helicobacter Infections enzymology, Helicobacter Infections microbiology, Helicobacter pylori enzymology, Humans, Infant, Pyloric Antrum enzymology, Pyloric Antrum pathology, Reproducibility of Results, Retrospective Studies, Gastritis diagnosis, Helicobacter Infections diagnosis, Helicobacter pylori isolation & purification, Immunohistochemistry methods, Silver Staining methods, Urease metabolism
Abstract

We compared immunohistochemical and silver stains of pediatric gastric biopsy sections for the identification of Helicobacter pylori infection with chronic inflammation and a negative urease screening test. Thirty-seven patients (age range 10 months to 21 years) whose gastric antral biopsies were negative for the rapid urease test (CLO(R)) but positive for lymphocytic infiltration were selected for a retrospective study. Specimens had been subjected to a rapid urease test (CLO(R)) and hematoxylin and eosin staining, and Dieterle silver staining and immunohistochemical staining specific for H. pylori were also performed. Twelve additional patients with urease-positive biopsies were used as controls. With Dieterle staining, 8/37 (22%) urease-negative biopsies contained organisms morphologically compatible with H. pylori, 21/37 (56%) contained organisms not compatible with H. pylori, and 8/37 (22%) were negative for organisms. Immunostaining confirmed 6/8 (75%) Dieterle-positive cases as being H. pylori, was negative in 2/8 (25%) Dieterle-positive cases, and was positive in 2/8 (25%) Dieterle-negative cases. Biopsies from 8/12 (67%) urease-positive specimens contained organisms seen with both Dieterle and immunohistochemical stains, and 4/12 (33%) were negative with both stains. Although both stains yielded comparable results with H. pylori-positive biopsies, Dieterle staining was potentially confusing because of nonspecific staining of other organisms. A significant proportion of (CLO(R))-negative biopsies was positive for H. pylori with special stains. We therefore recommend the use of immunohistochemical staining rather than silver staining in the evaluation of urease-negative gastric biopsies demonstrating chronic inflammation in children.

Published
2001
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18. Regulation of apolipoprotein secretion by biliary lipids in newborn swine intestinal epithelial cells.

Author

Wang H, Roberson R, Du J, Eshun JK, Berschneider HM, and Black DD

Subjects
Animals, Apolipoprotein A-I genetics, Apolipoprotein A-I metabolism, Apolipoproteins B metabolism, Cell Line, Cholesterol pharmacology, Intestinal Mucosa cytology, Phosphatidylcholines pharmacokinetics, Phosphatidylcholines pharmacology, RNA, Messenger metabolism, Swine, Taurocholic Acid pharmacokinetics, Taurocholic Acid pharmacology, Triglycerides metabolism, Animals, Newborn physiology, Apolipoproteins metabolism, Bile metabolism, Intestinal Mucosa metabolism, Lipids physiology
Abstract

Biliary lipids, composed of bile acids, cholesterol, and phosphatidylcholine, are a major source of luminal lipid in the small intestine. In the present study in a newborn swine intestinal epithelial cell line (IPEC-1), taurocholate and phosphatidylcholine were found to have no effect on apolipoprotein B (apo B) secretion but did significantly increase the basolateral secretion of apo A-I. This regulation of apo A-I secretion occurred at the pretranslational level for taurocholate and at the posttranslational level for phosphatidylcholine. The regulation of apo A-I secretion by phosphatidylcholine did not involve changes in apo A-I degradation and may involve mobilization of a preformed pool of apo A-I. Cholesterol, whether solubilized with taurocholate or phosphatidylcholine, had no effect on the secretion of either apo B or apo A-I. However, when taurocholate, phosphatidylcholine, and cholesterol were combined, apo B secretion was decreased, and the increase in apo A-I secretion noted with taurocholate and phosphatidylcholine alone was ablated. Another primary bile acid, taurochenodeoxycholate, was found to decrease apo B secretion but had no effect on apo A-I secretion. However, the significance of this effect is uncertain, since this bile acid caused significant cellular membrane injury, as evidenced by increased apical medium lactate dehydrogenase activity. Phosphatidylcholine, but not taurocholate, dramatically increased the basolateral secretion of radiolabeled phospholipid with a modest increase in cellular triglyceride radiolabeling. Furthermore, this effect of phosphatidylcholine on lipid synthesis did not require significant hydrolysis or uptake of the phosphatidylcholine molecule. Studies using radiolabeled taurocholate did not demonstrate active transport of taurocholate by these cells.

Published
1999
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